Pharmaceutical solution formulations for pressurised metered dose inhalers

ABSTRACT

The invention relates to the prevention and/or treatment of a severe broncho-pulmonary disease by administering a solution formulation from a pressurized metered dose inhaler capable of providing therapeutical doses of two or more active drug substances to the lung, wherein all the active drug substances are fully dissolved in the formulation as well as the two or more active drug substances are delivered with substantially the same particle size distribution.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2007/003420, filed on Apr. 19, 2007, and claims priority toU.S. patent application Ser. No. 11/408,026, filed on Apr. 21, 2006,both of which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods for the prevention or treatmentof a severe broncho-pulmonary disease by administering a solutionformulation from pressurized metered dose inhalers (pMDIs) which iscable of providing therapeutic doses of two or more active drugsubstances to the lungs, in which substantially all of the liquidparticles emitted on actuation of the inhaler contain the two or moreactive drug substances in a ratio which is substantially the same as apredetermined ratio of the two or more active drug substances in themedicament and the two or more active drug substances are delivered withsubstantially the same particle size distribution.

2. Discussion of the Background

Treatment of broncho-pulmonary diseases such as asthma and chronicobstructive pulmonary disease (COPD) with inhaled aerosol drugs offersadvantages over systemic therapy, including a more rapid onset andreduced adverse effects, because of the direct targeting of the lungs.

Pressurised metered dose inhalers (pMDIs) are well known devices foradministering pharmaceutical products to the respiratory tract byinhalation. MDIs use a propellant to expel droplets containing thepharmaceutical product to the respiratory tract as an aerosol.Formulations for aerosol administration via MDIs can be solutions orsuspensions. Solution formulations offer the advantage of beinghomogeneous, with the active ingredient and excipients completelydissolved in the propellant vehicle or its mixture with one or moresuitable co-solvents such as ethanol. Solution formulations also obviatethe physical stability problems associated with suspension formulationsthereby assuring more consistent uniform dosage administration.

Drugs commonly delivered by inhalation for treating broncho-pulmonarydiseases include short-acting and long-acting beta₂-agonists,anticholinergics/antimuscarinic agents, and corticosteroids inhydrofluoroalkane (HFA) propellants.

In particular, long-acting β₂-agonists (LABAs) such as formoterol andsalmeterol and antimuscarinic agents, such as selective muscarinicreceptors 3M antagonists, in combination with inhaled corticosteroids(ICS), have been proposed for the prevention and/or treatment of saiddiseases. However, despite modern maintenance treatments, some patientsare still under treated particularly when the broncho-pulmonary diseaseis in a severe form.

Hence there is still an unmet need for medicaments more efficacious forthe prevention or treatment of severe forms of broncho-pulmonarydiseases, in particular of sever forms of asthma and COPD.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelmedicaments which are useful for the prevention and/or treatment ofsevere forms of broncho-pulmonary diseases, in particular of severeforms of asthma and COPD.

It is another object of the present invention to provide novel methodsfor the prevention and/or treatment of severe forms of broncho-pulmonarydiseases, in particular of severe forms of asthma and COPD.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat more efficacious medicaments are obtained by providing pressurizedsolution formulations of two or more drug substances that, uponactuation of the inhaler deliver the active drug substances in a ratiowhich is substantially the same as the predetermined ratio of saidactive drug substances in the medicament and the active drug substancesare delivered with substantially the same particle size distribution.

In this way a co-deposition within the lung of the combination of theactive drug substances is obtained which results in a clinical responseof lung function that is greater than the sum of the response of theindividual drugs administered.

Thus, the present invention provides methods for the prevention and/ortreatment of a severe broncho-pulmonary diseases, which compriseadministering a pressurized solution formulation from a metered doseinhaler, which contains two or more active drug substances in apredetermined ratio dissolved in an HFA propellant and ethanol as aco-solvent, wherein, on actuation of the inhaler, substantially all ofthe liquid particles emitted contain the two or more active drugsubstances in a ratio which is substantially the same as thepredetermined ratio of the two or more active drug substances in themedicament and the two or more active drug substances are delivered withsubstantially the same particle size distribution.

The present invention also provides methods of preventing and/ortreating a severe broncho-pulmonary disease, which compriseadministering a combination of two or more active drug substances to thelung region tract of a subject by actuation of a pressurized singlemetered dose inhaler which contains the two or more active drugsubstances in a predetermined ratio and dissolved in an HFA propellantand ethanol as a co-solvent, wherein, on actuation of the inhaler,substantially all of the liquid particles emitted contain the two ormore active drug substances in a ratio which is substantially the sameas the predetermined ratio of the two or more active drug substances andthe two or more active drug substances are delivered with substantiallythe same particle size distribution.

The present invention further provides methods of preventing and/ortreating a severe broncho-pulmonary disease, which compriseadministering a pressurized solution formulation from a metered doseinhaler, which contains two or more active drug substances in apredetermined ratio dissolved in an HFA propellant and not more than 20%w/w ethanol as a co-solvent, wherein, on actuation of the inhaler,substantially all of the liquid particles emitted contain the two ormore active drug substances in a ratio which is substantially the sameas the predetermined ratio of the two or more active drugs and the twoor more active drug substances are delivered with substantially the sameparticle size, thereby improving the co-deposition of said drugs in thelung tract of a patient and therefore their synergistic interaction.

The present invention also provides metered dose inhalers, which containtwo or more active drug substances in a predetermined ratio dissolved inan HFA propellant and ethanol as a co-solvent, wherein, on actuation ofthe inhaler, substantially all of the liquid particles emitted containthe two or more active drug substances in a ratio which is substantiallythe same as the predetermined ratio of the two or more active drugsubstances and the two or more active drug substances are delivered withsubstantially the same particle size distribution.

The present invention also provides pressurized single metered doseinhalers which contain two or more active drug substances in apredetermined ratio and dissolved in an HFA propellant and ethanol as aco-solvent, wherein, on actuation of the inhaler, substantially all ofthe liquid particles emitted contain the two or more active drugsubstances in a ratio which is substantially the same as thepredetermined ratio of the two or more active drug substances and thetwo or more active drug substances are delivered with substantially thesame particle size distribution.

The present invention further provides metered dose inhalers, whichcontain two or more active drug substances in a predetermined ratiodissolved in an HFA propellant and not more than 20% w/w ethanol as aco-solvent, wherein, on actuation of the inhaler, substantially all ofthe liquid particles emitted contain the two or more active drugsubstances in a ratio which is substantially the same as thepredetermined ratio of the two or more active drugs and the two or moreactive drug substances are delivered with substantially the sameparticle size, thereby improving the co-deposition of said drugs in thelung tract of a patient and therefore their synergistic interaction.

Preferably the active drug substances comprise a bronchodilating and/oranti-inflammatory compound, more preferably a long acting beta₂-agonistand an inhaled corticosteroid.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same become betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 shows the cumulative % undersize BDP and FF mass distributionsfor the sample as determined in Example 1; and

FIG. 2 shows the percentage (of metered dose) ACI stage by stagedeposition of LABA and ICS (bars represents Mean±SD; (n=6)) as measuredin Example 2.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the expression “on actuation of the inhaler,substantially all of the liquid particles emitted contain the two ormore active drug substances in a ratio which is substantially the sameas the predetermined ratio of the two or more active drug substances”means that the relative standard deviation (RSD) of the ratio of theamounts of drugs measured along the stages of an Andersen CascadeImpactor (ACI) is less than 5.0%, preferably less than 3.5%, morepreferably less than 2.0%, when the active drug substances are deliveredat doses comprised between 4 and 16 μg, while it is less than 15%,preferably less than 12%, when at least one of the active ingredient isdelivered at a dose higher than 0.5 but lower than 4 μg. This isbecause, from an experimental standpoint, it is more difficult todetermine the ratio in a precise way when one or more of the activeingredients is delivered at a low dose.

The relative standard deviation (RDS) is calculated by the formula:(SD/mean)*100.

As used herein the expression “the two or more active drug substancesare delivered with substantially the same particle size” means that theparticle size distributions of the drugs determined along the stages ofthe Andersen Cascade Impactor (ACI) are not statistically significantlydifferent (p<0.05).

As used herein the term “dose” means the amount of active ingredientdelivered by a single actuation of the inhaler.

As used herein, the expression “% w/w” means the weight percentage ofthe component in respect to the total weight of the composition.

According to the Global INitiative for Asthma (GINA), severe persistentasthma is defined as a form characterized by daily symptoms, frequentexacerbations, frequent nocturnal asthma symptoms, limitation ofphysical activities, forced expiratory volume in one second (FEV₁) equalto or less than 60% predicted and with a variability higher than 30%.

According to the Global initiative for chronic Obstructive PulmonaryDisease (GOLD) guidelines, severe COPD is a form characterized by aratio between FEV₁ and the Forced Vital Capacity (FVC) lower than 0.7and FEV₁ between 30% and 50% predicted. The very severe form is furthercharacterized by chronic respiratory failure.

The particle size distribution (PSD) data of the pMDI formulations havebeen obtained using an Andersen Cascade Impactor (ACI) in accordancewith the European Pharmacopoeia 5th Edition 2007, part 2.9.18, page3109, and in particular according to the procedure described in detailin Example 1.

The level of co-deposition may be monitored by a scintigraphic studywhich permits evaluation of the distribution of the active substancesalong the various lung areas, i.e. from the central to the peripheralairways.

Formulations, which upon actuation of the pressurized metered doseinhaler, on evaporation of the propellant mixture, feature an averageparticle size of the two active ingredients equal or below 1.1micrometer are also referred to herein as extrafine.

The medicaments of the present invention are obtained by providingsolution formulations of two or more drug substances to be used withpressurized metered dose inhalers (pMDIs) that, upon actuation of theinhaler deliver the active drug substances in a ratio which issubstantially the same as the predetermined ratio of said active drugsubstances in the medicament and the active drug substances aredelivered with substantially the same particle size distribution atstages. In fact this allows achieving a co-deposition within the lung ofthe combination of the active drug substances which results in aclinical response of lung function that is greater than the sum of theresponse of the individual drugs administered. Co-deposition in the samelung region indeed maximizes the synergistic effects, with a greatimprovement in the lung function of the patients.

The solution formulations to be used with pMDIs of the present invention(hereinafter pressurized solution formulations), comprise an ethanol/HFApropellant based solution formulation for aerosol administrationcontaining a combination of two or more active drug substances, whereinsaid active drug substances are fully dissolved in the formulation, eachliquid particle generated during the MDIs atomisation process containsdrug concentrations consistent with the liquid properties of theproduct's solution formulation and that this consistency is maintainedfor the residual particles following excipient evaporation.

Moreover it has been found that each droplet of the aerosol cloudemitted on actuation of the inhaler containing a solution of differentactive drug substances dries to give particles of the active materialswith identical size distributions in the correct ratio.

This characteristic is maintained through the life of the inhalerdevice.

It is now surprisingly been found that the formulations described aboveare particularly useful for the prevention and/or treatment of a severebroncho-pulmonary disease, especially severe persistent asthma andsevere COPD.

It is preferred that the solution formulation be suitable for deliveringthe therapeutic daily doses of the active ingredients in one or twoactuations.

Advantageously the solution formulation is suitable for delivering atleast one of the active ingredients at a dose lower than 20 μg. Inparticular, in certain embodiments, the dose of at least one of theactive ingredient to be delivered shall be comprised between 4 and 16μg, preferably 6 or 12 μg, more preferably 6 μg. In other embodiments,the dose of at least one of the active ingredient shall be higher than0.5 but lower than 4 μg, preferably 1 or 2 μg, more preferably 1 μg.

Active ingredients which may be used in the aerosol formulations of theinvention are short- and long-acting beta₂-adrenergic agonists,preferably long-acting beta₂-adrenergic agonists such as formoterol,salmeterol, indacaterol, carmoterol and salts thereof and theircombinations with other active ingredients, preferably selected from thegroup of inhaled corticosteroids (ICS) or anticholinergic atropine-likederivatives, antimuscarinic M3 inhibitors, or phosphodiesterase 4 (PDE4)inhibitors.

Preferred ICS are beclomethasone dipropionate, budesonide and its22R-epimer, rofleponide, ciclesonide, fluticasone propionate, mometasonefuroate or triamcinolone and its ester such as triamcinolone acetonide.In a preferred embodiment, the ICS is budesonide or an epimer thereof.In another preferred embodiment, the ICS is beclometasone dipropionate.

Preferred anticholinergic atropine-like derivatives are ipratropiumbromide, oxitropium bromide, tiotropium bromide, or glycopyrroniumbromide.

Preferred long acting beta₂-agonists are formoterol, carmoterol, andsalmeterol, and salts thereof.

More preferably, the first active ingredient is a long actingbeta₂-agonists belonging to the formula sketched below

wherein R is 1-formylamino-2-hydroxy-phen-5-yl (formoterol) or8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) or one of their salts,solvates, solvates of the salts or stereoisomers.

In a particular embodiment, the solution formulation will be suitablefor delivering 6 or 12 μg/dose of formoterol fumarate, more preferably 6μg. In another embodiment, the solution formulation will beadvantageously suitable for delivering 0.5 to 4 μg/dose, preferably 0.5to 2 μg/dose, more preferably about 1 μg/dose of carmoterolhydrochloride (TA 2005).

The ratios in which the beta₂-agonist and the other active drugsubstance may be used in the solution formulation are variable.Depending on the choice of the active drug substance, the ratios byweight which may be used within the scope of the present invention varyon the basis of the different molecular weights of the varioussubstances and their different potencies.

Advantageously, the pressurized solutions according to the invention maycontain the beta₂-agonist and the other active drug substance in ratiosby weight ranging from 1:2 to 1:3200.

In certain embodiments, wherein the other active substance is an ICS, ifthe beta₂-agonist is delivered at a dose comprised between 4 and 16 μg,the ratio shall range between 1:3 and 1:100, preferably between 1:8 and1:40.

In other embodiments, if the beta₂-agonist is delivered at a dosecomprised higher than 0.5 but lower than 4 μg, the ratio by weight shallrange between 1:12.5 and 1:800, preferably between 1:25 and 1:400.

When the other active drug substance present in the solution formulationis budesonide, said formulation will be suitable for delivering 50 to400 μg/dose, preferably 100 to 200 μg/dose, more preferably 100 or 200μg/dose, of said drug substance.

When the other active drug substance is beclometasone dipropionate, theformulation will be suitable for delivering 50 to 200 μg/dose,preferably 100 or 200 μg/dose.

The hydrofluorocarbon propellant is preferably selected from the groupof HFA 134a, HFA 227, and mixtures thereof.

Advantageously the amount of ethanol in the solution formulation iscomprised between 5% and 20% w/w, more advantageously between 6% and 18%w/w, preferably comprised between 8 and 16% w/w, more preferably theamount of ethanol is 12% or 15% w/w.

The solution formulation of the invention may further contain smallamounts of a mineral acid to adjust the apparent pH to between 2.5 and5.0 wherein apparent is defined in the European Patent Application No.EP 1 157 689.

Preferably the solution formulations of the present invention arecapable of delivering, on actuation of the inhaler, an average fractionof particles of the active ingredients equal to or less than 1.1 micron,allowing the drugs to reach the small peripheral airways region wherethey exercise their pharmacological effects. Herewith the formulationsfeaturing these characteristics will be defined as extrafine.

The solution formulations of the invention may be contained in apressurized MDI having part of all of the internal metallic surfacesmade of anodized aluminium, stainless steel or lined with an inertorganic coating. Examples of preferred coatings are epoxy-phenol resins,perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes suchas polytetrafluoroethylene, fluorinated-ethylene-propylene, polyethersulfone, and a mixture of fluorinated-ethylene-propylene and polyethersulfone. Other suitable coatings could be polyamide, polyimide,polyamideimide, polyphenylene sulphide, or their combinations.

According to a particular embodiment of the invention, there is provideda pressurised MDI consisting of an aluminium container filled with aformulation consisting of an extrafine solution of formoterol fumaratein combination with beclometasone dipropionate in HFA 134a as apropellant in turn containing 12% w/w ethanol as a co-solvent, theapparent pH of said solution having been adjusted to between 3.0 and 5.0by addition of a suitable amount of hydrochloric acid.

According to a further particular embodiment of the invention, there isprovided a pressurised MDI consisting of a coated container filled witha formulation consisting of an extrafine solution of8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinonehydrochloride (TA 2005) in combination with budesonide in HFA 134a as apropellant in turn containing 15% w/w ethanol as a co-solvent, theapparent pH of said solution having been adjusted to between 3.0 and 5.0by addition of a suitable amount of phosphoric acid.

Advantageously, all the pressurized solution formulations of the presentinvention are filled in a device, such as an aerosol inhaler, accordingto a method comprising the following steps:

(a) preparing of a solution of one or more active ingredients in one ormore co-solvents;

(b) filling of the device with said solution;

(c) optionally adding a pre-determined amount of a strong mineral acid;

(d) adding a propellant containing a hydrofluoroalkane (HFA); and

(e) crimping with valves and gassing.

The formulation is actuated by a metering valve capable of delivering avolume of between 50 μl and 100 μl.

Metering valves fitted with gaskets made of chloroprene-based rubberscan preferably be used to reduce the ingress of moisture which, aspreviously mentioned, can adversely affect the stability of the drugduring storage. Optionally, further protection can be achieved bypackaging the product in a sealed aluminium pouch.

The pressurized solution formulations having the features described inthe present invention, in particular those comprising a long-actingβ2-agonist (LABA) bronchodilator and an inhaled corticosteroid (ICS) areuseful in the prevention and/or treatment of a severe broncho-pulmonarydisease, in particular severe persistent asthma and severe and verysevere chronic obstructive pulmonary disease (COPD).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Particle Size Distribution for Formoterol Fumarateand Beclometasone Dipropionate within an Ethanol Based Solution HFA pMDIby Andersen Cascade Impactor (ACI)

The solution formulation contained beclometasone dipropionate (“BDP”)(100 μg/dose) and formoterol fumarate (“FF”) (6 μg/dose) in 50 μl in HFA134a propellant vehicle with 12% w/w ethanol as cosolvent and 0.024% w/whydrochloric acid (1M) as stabilizer. The formulation was packed in cansfitted with 50 μl valves and fired using a 0.30 mm actuator. Aerodynamicparticle size assessments were conducted using an Andersen CascadeImpactor fitted with a USP induction port at the beginning and end ofcan-use life from each of two batches. Each determination was obtainedby sampling 15 consecutive doses at a sampling flow rate of 28.3l/minute. For each can tested the delivered dose was determined usingDUSA methodology (Dose Unit Spray Apparatus) at the beginning, middle,and end of can-use life. Quantification of BDP and FF within testsamples was performed using a HPLC method. Metered dose, delivered dose,fine particle dose, fine particle fraction, mass median aerodynamicdiameter (MMAD), and geometric standard deviation (GSD) for eachimpactor measurement were calculated.

Aerosol performances derived from impactor measurements are summarisedin Table 1. For BDP and FF respectively, the mean delivered dose valuesobtained from the impactor measurements were within 95 to 100% and 91 to101% of the mean values obtained using DUSA methodology. The consistencyin the fine particle fraction (both≦5 μm and ≦1 μm), MMAD and GSD forBDP and FF is a consequence of the similar particle size distributionsof the two drugs as shown in FIG. 1 (not statistically significantlydifferent).

TABLE 1 Summary of Aerosol Performances. Data represents Mean ± SD; (n =4). Drug BDP FF Metered Dose, MD (μg) 94.5 ± 2.3 5.4 ± 0.3 DeliveredDose (μg) 87.0 ± 2.2 4.9 ± 0.3 Fine particle dose ≦5 μm (μg) 34.5 ± 1.1 1.9 ± <0.1 Fine particle fraction ≦ 5 μm (%) 39.7 ± 2.2 38.6 ± 2.2 Fine particle dose ≦ 1 μm (μg) 11.1 ± 0.2  0.6 ± <0.1 Fine particlefraction ≦ 1 μm (%) 12.8 ± 0.4 11.8 ± 0.5  MMAD (μm)  1.4 ± <0.1  1.5 ±<0.1 GSD  2.0 ± 0.1 2.0 ± 0.1 Shot Weight (mg) 54.0 ± 1.3

Table 2 presents the mean drug deposition for samples containing >5% ofthe metered dose, the total being representative of 94.5±5.4% of thetotal metered drug mass. The ratio of BDP to FF presented in Table 2,expressed as mean and standard deviation, is 17.6±0.3, which isconsistent with the ratio of metered BDP and FF (17.6±0.6). Theconsistent ratio of the drug masses over the size fractions implies thateach particle generated during the atomisation process contains drugconcentrations consistent with the liquid properties of the product'ssolution formulation, and that this consistency is maintained for theresidual particles following excipient evaporation, such that themeasured particle size distributions for both resident drugs areidentical.

TABLE 2 ACI stage-by-stage deposition. Data represents Mean ± SD; (n =4). Ratio: Deposition site BDP (μg) FF (μg) BDP/FF Actuator 7.5 ± 0.30.43 ± 0.03 17.6 Induction Port 49.5 ± 3.2  2.89 ± 0.23 17.1 Stage 4 5.9± 0.3 0.33 ± 0.01 17.8 (2.1-3.3 μm) Stage 5 14.2 ± 0.8  0.80 ± 0.03 17.7(1.1-2.1 μm) Stage 6 6.4 ± 0.3 0.36 ± 0.01 17.8 (0.65-1.1 μm) Total:83.6 ± 4.9  4.82 ± 0.32 Mean ± SD: 17.6 ± 0.3

Example 2 Solution Combination Containing Carmoterol Hydrochloride (TA2005) as LABA and Budesonide (BUD) as ICS

The LABA TA 2005 is present in the combination at a strength of 1μg/dose per actuation while budesonide is present at 100 μg/dose peractuation within an acidified ethanol solution pressurized with HFA134a. Aerodynamic assessment of fine particles was performed by sampling10 consecutive doses from each pMDI into an ACI. The impactor was fittedwith a USP induction port and operated at a sampling flow rate of 28.3l/minute. Three pMDIs were tested (from the beginning, middle, and endof batch) and were tested at the beginning and end of life. Drugdeposition within the impactor was quantified using an HPLC assay. Thefine particle dose (FPD) was determined by summation of the drugcollected on the ACI stages between S3 and filter.

Table 3 summarizes the deposition of TA 2005 and budesonide on theindividual stages of the ACI, while Table 4 summarizes the aerosolperformances. The nominal dose of the combination pMDI was 1 μg TA 2005:100 μg budesonide. FIG. 2 summarizes these results expressed as the %metered dose.

TABLE 3 ACI stage-by-stage deposition. Data represents Mean ± SD; (n =6). Deposition TA 2005 Ratio: site (μg) BUD (μg) BUD/TA 2005 Actuator0.08 ± 0.02 6.68 ± 1.14 83.5 Induction 0.40 ± 0.03 38.16 ± 2.29  95.4port Stage 4 0.05 ± 0.01 5.45 ± 0.83 109.0 Stage 5 0.18 ± 0.02 18.5 ±1.83 102.8 Stage 6 0.11 ± 0.01 10.8 ± 0.75 98.2 Mean ± SD: 97.8 ± 9.5

TABLE 4 Summary of Aerosol Performances. Data represents Mean ± SD (n =6). Drug BUD TA 2005 Delivered Dose (μg) 89.7 ± 3.2  089 ± 0.03 Fineparticle dose ≦ 5 μm (μg) 47.1 ± 2.7 0.45 ± 0.03 Fine particle fraction≦ 5 μm (%) 52.5 ± 2.3 51.0 ± 3.0 

The results demonstrate that the solution combination of the exampleprovides fine particle fractions for the two components which are notstatistically significantly different (p<0.05), despite thesignificantly different concentration of the two active drugs in theaerosol cloud. The ratio between the two active drugs is maintained inall the ACI stages allowing their co-deposition in the lungs, whichcould offer an increased opportunity for any synergistic interaction tooccur.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A method for the prevention and/or treatment of a severebroncho-pulmonary disease, which comprises administering to a subject inneed thereof an effective amount of a pressurized solution formulationfrom a metered dose inhaler, which comprises two or more active drugsubstances in a predetermined ratio dissolved in an HFA propellant and aco-solvent, wherein, on actuation of said inhaler, substantially all ofthe liquid particles emitted contain said two or more active drugsubstances in a ratio which is substantially the same as saidpredetermined ratio of said two or more active drug substances and saidtwo or more active drug substances are delivered with substantially thesame particle size distribution.
 2. The method according to claim 1,wherein said formulation comprises at least one beta₂-agonist.
 3. Themethod according to claim 1, wherein said formulation comprises at leastone member selected from the group consisting of formoterol, carmoterol,indacaterol salmeterol, stereoisomers, a salt thereof, a solvatethereof, a solvate of a salt thereof, and mixtures thereof.
 4. Themethod according to claim 1, wherein said formulation comprisesformoterol fumarate.
 5. The method according to claim 1, wherein saidformulation comprises carmoterol hydrochloride.
 6. The method accordingto claim 1, wherein said formulation comprises an inhaledcorticosteroid.
 7. The method according to claim 1, wherein saidformulation comprises at least one member selected from the groupconsisting of beclomethasone dipropionate, fluticasone propionate,budesonide, the 22R-epimer of budesonide, rofleponide, ciclesonide,mometasone furoate, triamcinolone, an ester of triamcinolone, andmixtures thereof.
 8. The method according to claim 1, wherein saidformulation comprises beclometasone dipropionate or budesonide.
 9. Themethod according to claim 1, wherein said formulation comprises ananticholinergic atropine-like derivative or an antimuscarinic M3inhibitor.
 10. The method according to claim 1, wherein said formulationcomprises at least one member selected from the group consisting ofipratropium bromide, oxitropium bromide, tiotropium bromide,glycopyrronium bromide, and mixtures thereof.
 11. The method accordingto claim 1, wherein said formulation comprises ethanol in an amountbetween 5% and 20% w/w, based on the total weight of said formulation.12. The method according to claim 1, wherein said broncho-pulmonarydisease is severe persistent asthma.
 13. The method according to claim1, wherein said broncho-pulmonary disease is severe or very severechronic obstructive pulmonary disease (COPD).
 14. A method for improvingthe co-deposition of two or more active drug substances in the lungtract of a patient, comprising administering a pressurized solutionformulation from a metered dose inhaler, which comprises two or moreactive drug substances in a predetermined ratio dissolved in an HFApropellant and not more than 20% w/w ethanol as a co-solvent, wherein,on actuation of said inhaler, substantially all of the liquid particlesemitted contain said two or more active drug substances in a ratio whichis substantially the same as said predetermined ratio of said two ormore active drugs and said two or more active drug substances aredelivered with substantially the same particle size.
 15. The methodaccording to claim 14, wherein said formulation comprises at least onebeta₂-agonist.
 16. The method according to claim 14, wherein saidformulation comprises at least one member selected from the groupconsisting of formoterol, carmoterol, indacaterol salmeterol,stereoisomers, a salt thereof, a solvate thereof, a solvate of a saltthereof, and mixtures thereof.
 17. The method according to claim 14,wherein said formulation comprises formoterol fumarate.
 18. The methodaccording to claim 14, wherein said formulation comprises carmoterolhydrochloride.
 19. The method according to claim 14, wherein saidformulation comprises an inhaled corticosteroid.
 20. A metered doseinhaler, which contains a solution formulation which comprises two ormore active drug substances in a predetermined ratio dissolved in an HFApropellant and ethanol as a co-solvent, wherein, on actuation of saidinhaler, substantially all of the liquid particles emitted contain saidtwo or more active drug substances in a ratio which is substantially thesame as said predetermined ratio of said two or more active drugsubstances and said two or more active drug substances are deliveredwith substantially the same particle size distribution.